medwireNews: Treatment with nivolumab may mitigate progression to oral squamous cell carcinoma (OSCC) in people with high-risk proliferative verrucous leukoplakia (PVL), suggest phase 2 trial data.
Glenn Hanna (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and colleagues report that the study met its primary endpoint of an overall response rate of at least 25%, “suggesting potential clinical activity for nivolumab in high-risk PVL.”
But they highlight that “few patients had complete lesion regression,” and add that it was a single-center trial that used “a novel clinical and pathologic scoring system to assess immunotherapy response in a hard-to-study oral precancer population.”
Therefore, “[a] next step would be to consider a larger, precision immunotherapy randomized clinical trial favoring CFS [cancer-free survival] as a primary outcome and stratified by prior history of early-stage treated OSCC and 9p21.3 loss,” they write in JAMA Oncology.
Outlining the background to the study, Hanna et al explain that PVL “is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive [OSCC].” A recent retrospective study conducted by the authors “revealed a cytotoxic T-cell–rich microenvironment, providing strong rationale to investigate immune checkpoint therapy.”
A total of 33 patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia) were recruited from the Dana-Farber Cancer Institute. Participants were aged a median of 63 years, 55% were women, 48% were smokers, and 24% had previously resected early-stage OSCC. They were given up to four doses of nivolumab 480 mg every 4 weeks and response was assessed using a modified composite scoring system (van der Waal classification) that evaluated both size and degree of dysplasia.
Thirty-six percent of participants achieved an overall response, defined as either a major or partial response, which corresponded to a decrease in the composite score from baseline of more than 80% and 40–80%, respectively. Just two (9%) patients had complete resolution of at least one lesion.
During the course of the study, nine (27%) participants developed OSCC, and interestingly, six of them had a history of early-stage OSCC. Of note, patients were also more likely to develop OSCC if they had 9p21.3 copy number loss, compared with no loss, at biopsy (60 vs 0%).
At a median follow-up of 21.1 months, median CFS was not reached in the overall cohort and the 2-year CFS rate was 72.8%, while the overall survival rate was 100%.
Noting that the previous retrospective study demonstrated a 2-year CFS rate of 82%, the researchers comment that “[i]t is plausible that our preliminary CFS rate would have been similar without immunotherapy exposure, supporting the need for randomized data.”
Adverse events of grade 3 or 4 occurred in 21% of participants, but all of them “later resolved,” says the team. The most common events of any grade were fatigue, oral pain, and diarrhea, in 55%, 33%, and 27%, respectively.
There were two cases of immune-related hepatitis and one of immune-related colitis, which occurred 5 months after completion of nivolumab therapy.
“These findings need to be weighed carefully against the potential for clinical activity, given concern for a narrow therapeutic risk-benefit ratio,” say Hanna and co-authors.
And they conclude: “Recognizing the limitations and complexity of measuring treatment outcomes in precancer trials, for the first time, we demonstrate potential clinical activity and acceptable safety with the use of [immune checkpoint therapy] in a population with high-risk precancer.”
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